ORGANIC LETTERS
Diphenylprolinol Silyl Ether as a Catalyst in an Asymmetric, Catalytic, and Direct Michael Reaction of Nitroethanol with r,β-Unsaturated Aldehydes
2009 Vol. 11, No. 18 4056-4059
Hiroaki Gotoh,† Daichi Okamura,† Hayato Ishikawa,† and Yujiro Hayashi*,†,‡ Department of Industrial Chemistry, Faculty of Engineering, and Research Institute for Science and Technology, Tokyo UniVersity of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
[email protected] Received June 30, 2009
ABSTRACT
Diphenylprolinol silyl ether was found to be an effective organocatalyst in the enantioselective and direct Michael reaction of nitroethanol and r,β-unsaturated aldehydes, affording the 1-hydroxy-trans-3,4-disubstituted tetrahydropyrans after isomerization. The generated Michael addition products are useful synthetic intermediates, which can be converted into chiral tetrahydropyran with a quaternary stereocenter, 3-substituted cis- and trans-prolines, and r-amino acid derivatives.
Enantiomerically pure R-amino acids are extremely important organic substances because they are found in many biologically active compounds. Accordingly, several methods have been developed for the synthesis of the enantiomerically pure R-monosubstituted R-amino acids.1 The Michael reaction of glycine equivalents and an electron-deficient alkene is one such method.2 Nitroethanol possesses nitro and hydroxy functionalities, which are easily transformed into amine and carboxylic acid †
Department of Industrial Chemistry, Faculty of Engineering. Research Institute for Science and Technology. (1) Najera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584. ‡
10.1021/ol901483x CCC: $40.75 Published on Web 08/26/2009
2009 American Chemical Society
moieties by reduction and oxidation, respectively. Thus, nitroethanol is regarded as a synthetic equivalent of the R-amino acid, glycine.3 In the past few years, organocatalysis has been intensively studied.4 Many types of organocatalysts with unique proper(2) (a) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347. (b) Akiyama, T.; Hara, M.; Fuchibe, K.; Sakamoto, S.; Yamaguchi, K. Chem. Commun. 2003, 1734. See the review: Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222. (3) (a) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shibasaki, M. J. Org. Chem. 1995, 60, 7388. (b) Sohtome, Y.; Kato, Y.; Handa, S.; Aoyama, N.; Nagawa, K.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10, 2231.
ties have been reported. Our group5 and Jørgensen and coworkers6 independently developed diarylprolinol silyl ether as an effective organocatalyst that has subsequently been widely used by many research groups.7 Just recently, we5e and Jørgensen’s group6c reported the asymmetric Michael reaction of 4-substituted-2-oxazolinone and R,β-unsaturated aldehydes catalyzed by diphenylprolinol silyl ether, which affords R,R-disubstituted R-amino acid equivalents with excellent enantioselectivity. As we previously reported, the asymmetric Michael reaction of nitroalkane and R,β-unsaturated aldehydes catalyzed by diphenylprolinol silyl ether5d,8 and nitroethanol was expected to react with R,β-unsaturated aldehydes, generating R-monosubstituted R-amino acid equivalents, the successful realization of which will be described in this communication. Our scenario is as follows: nitroethanol should react with R,β-unsaturated aldehyde to generate the Michael adduct, γ-nitroaldehyde, which would cyclize to afford substituted tetrahydropyrans 2 and 3. Although diastereoselectivity of 2 and 3 is expected to be low in view of the previous results for nitroethane in which low diastereoselectivity is obtained,5d isomerization would convert cis-isomer 3 into the more thermodynamically stable trans-isomer 2 (eq 1, Scheme 1). Tetrahydropyran 2 would be a useful synthetic
Scheme 1
intermediate with several functional groups for the synthesis of nitrogen-containing molecules. To realize this scenario, the reaction of cinnamaldehyde and nitroethanol was selected as a model, and the Michael reaction was examined using diphenylprolinol trimethylsilyl ether 1 as a catalyst in the presence of benzoic acid in MeOH.5d Four diastereomers of tetrahydropyran derivatives 2ar, 2aβ, 3ar, and 3aβ were obtained quantitatively. Trans-2a (4) For reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Asymmetric Organocatalysis; Berkessel, A., Groger, H., Eds.; Wiley-VCH: Weinheim, 2005. (c) Hayashi, Y. J. Synth. Org. Chem. Jpn. 2005, 63, 464. (d) List, B. Chem. Commun. 2006, 819. (e) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 2001. (f) Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug DiscoVery Today 2007, 12, 8. (g) EnantioselectiVe Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007. (h) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471. (i) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (j) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. (5) (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (b) Gotoh, H.; Masui, R.; Ogino, H.; Shoji, M.; Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 6853. (c) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem., Int. Ed. 2007, 46, 4922. (d) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307. (e) Hayashi, Y.; Obi, K.; Ohta, Y.; Okamura, D.; Ishikawa, H. Chem. Asian J. 2009, 4, 246, and the references cited therein. Org. Lett., Vol. 11, No. 18, 2009
and cis-3a isomers were partially separated by column chromatography and the enantiomeric excess of 2ar and 2aβ, and those of 3ar and 3aβ were found to be the same and excellent values (eq 2, Scheme 2). By the use of the partially
Scheme 2
separated isomers 2a and 3a, the isomerization of 2a and 3a was investigated under several basic conditions. When a mixture of 2a and 3a (2a:3a ) 22:78) was treated with inorganic bases such as K2CO3, CaCO3, KHCO3, NaHCO3, and Cs2CO3 in MeOH, NaHCO3 was found to be effective in affording the mixture, in which the trans-isomer is formed predominantly (2a:3a ) 89:11) with good conversion yield. When pure trans-isomer 2a was treated under the same conditions, a mixture of trans- and cis-isomers was obtained with the same ratio (2a:3a ) 89:11, eq 3). These results indicate that there is equilibrium between trans- and cisisomers and that its ratio is 89:11 in MeOH. Michael and isomerization reacions can be performed in a single-pot operation. That is, after the treatment of cinnamaldehyde and nitroethanol with 1 and PhCO2H at room temperature for 20 h, addition of NaHCO3 to the reaction mixture and further stirring for 48 h afforded tetrahydropyran derivatives 2a and 3a in good yield with high diastereoselectivity and excellent enantioselectivity (Table 1, entry 1). After the reaction conditions were optimized, the generality of the reaction was investigated, and the results are summarized in Table 1. The reaction has broad applicability. Not only phenyl but also the 2-naphthyl-substituted acrolein (6) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (b) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjasgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703. (c) Cabrera, S.; Reyes, E.; Aleman, J.; Milelli, A.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem. Soc. 2008, 130, 12031. For recent reports, see: (d) Jiang, H.; Falcicchio, A.; Jensen, K. L.; Paixao, M. W.; Bertelsen, S.; Jørgensen, K. A. J. Am. Chem. Soc. 2009, 131, 7153. (7) For selected examples of other group’s application of diarylprolinol ether, see: (a) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861. (b) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios, R.; Cordova, A. Angew. Chem., Int. Ed. 2007, 46, 778. (c) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc. 2007, 129, 10886. (d) Enders, D.; Narine, A. A.; Benninghaus, T. R.; Raabe, G. Synlett 2007, 1667. (e) Vo, N. T.; Pace, R. D. M.; O’Hara, F.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 404. For a review, see: (f) Palomo, C.; Mielgo, A. Angew. Chem., Int. Ed. 2006, 45, 7876. (g) Mielgo, A.; Palomo, C. Chem. Asian J. 2008, 3, 922. (8) Other group’s Michael reaction, see: (a) Zu, L.; Xie, H.; Li, H.; Wang, J.; Wang, W. AdV. Synth. Catal. 2007, 349, 2660. (b) Wang, Y.; Li, P.; Liang, X.; Zhang, T. Y.; Ye, J. Chem. Commun. 2008, 1232. 4057
BF3·OEt2 to afford the trans-3,4-disubstituted tetrahydropyran 5 in 93% yield (eq 5, Scheme 3). When hydroxypyran 2
Table 1. One-Pot Michael and Isomerization Reaction of R,β-Unsaturated Aldehyde and Nitroethanola
Scheme 3
entry
R
1 2 3 4 5 6 7 8 9 10 11 12
Ph Ph 2-naphthyl p-NO2C6H4p-BrC6H4p-MeOC6H4o-MeOC6H4furyl thienyl PhCH2CH2 cyclohexyl isobutyl
X Y time (mol %) (mol %) (h)b 10 2 10 10 10 10 10 10 10 10 20 20
20 4 20 20 20 20 20 20 20 0 0 0
20 46 28 15 15 26 21 26 21 27 79 71
2:3c 89:11 84:16 87:13 86:14 86:14 84:16 85:15 80:20 90:10 76:24 76:24 78:22
yield ee (%)d (%)e 86 87 92 80 85 95 94 80 82 76 55 72
95 96 94 99 93 93 94 91 94 92 96 92
a The reaction conditions: R,β-unsaturated aldehyde (0.60 mmol), nitroethanol (0.90 mmol), catalyst 1 (0.060 mmol), PhCO2H (0.12 mmol), and NaHCO3 (3.0 mmol) in MeOH (1.2 mL) were employed. See the Supporting Information in detail. b The reaction time for the first Michael reaction. c Diastereomeric ratio was determined by 1H NMR or 13C NMR. d Yield of isolated products 2 and 3. e Enantiomeric excess of 2, which was determined by chiral HPLC analysis after conversion to the corresponding acetyl ester.
derivative gave an excellent result (entry 3). When the substituent is electron deficient, such as p-nitro or pbromophenyl, the reaction also proceeds efficiently, generating the substituted tetrahydropyrans with good diastereoselectivities and excellent enantioselectivities (entries 4 and 5). Acrolein derivatives possessing electron-rich aromatic substituents such as p- and o-methoxyphenyl are also good substrates, generating excellent results (entries 6 and 7). Not only aromatic groups but also heteroaromatic groups such as furyl and thienyl are suitable substituents (entries 8 and 9). Alkyl-substituted acroleins were employed successfully, in which better results were obtained without the addition of PhCO2H. That is, the reaction of acroleins possessing 2-phenylethyl, cyclohexyl, and isobutyl moieties proceeds in the presence of catalyst 1, affording the tetrahydropyran derivatives with excellent enantioselectivity (entries 10-12). Although we used 10 mol % of the catalyst, the catalyst loading can be reduced to 2 mol %. Namely, in the presence of 2 mol % of 1 and 4 mol % of benzoic acid, the reaction of cinnamaldehyde proceeded efficiently, affording the desired product in 87% yield without compromising the enantioselectivity (96% ee, entry 2). The substituted tetrahydropyran 2 is a useful synthetic intermediate because it possesses several functional groups, the transformations of which were investigated next. Tetrahydropyran 2 was converted into acetoxytetrahydropyran 4, which was reduced with Et3SiH in the presence of 4058
was treated with H2 in the presence of Pd(OH)2, reduction of the nitro group and a successive intramolecular reductive amination occurred to provide the pyrrolidine derivative, which was isolated as the N-Boc-protected 2,3-cis-disubstituted pyrrolidine 6 in 80% yield over two steps. Oxidation with o-iodoxybenzoic acid (IBX)9 gave cis-aldehyde 7, which was further oxidized under Kraus conditions10 to provide cis-3-phenylproline derivative 8 (eq 6). On the other hand, trans-aldehyde 9 was obtained by the isomerization of cisisomer 7 with DBU, followed by oxidation to afford trans3-phenylproline derivative 10 (eq 7). By these methods, (9) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem. 1995, 60, 7272. (10) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825. Org. Lett., Vol. 11, No. 18, 2009
cis- and trans-3-substituted prolines can be synthesized stereoselectively from the same starting material. The absolute configuration of the methyl ester of 8 was determined by a comparison of its optical rotation with that of the literature.11 When acetoxytetrahydropyran 4 was treated with methyl acrylate in the presence of Cs2CO3, the Michael reaction proceeded smoothly to generate the product 11 as a single isomer. It should be noted that the reaction proceeds with excellent diastereoselectivity with the generation of a quaternary stereocenter (eq 8). When acetoxytetrahydropyran 4 was reduced with H2 in the presence of Pd(OH)2, the amine was generated, which was treated with ZCl and i-Pr2EtN to afford 12 in 83% yield over two steps. Hydrolysis of the ester, followed by the Wittig reaction, afforded amino alcohol 13. By oxidation of the alcohol to the carboxylic acid and conversion of the carboxylic acid to the ester, R-amino ester derivative 14 was synthesized stereoselectively (eq 9). In summary, we report that 1-hydroxy-trans-3,4-disubstituted tetrahydropyrans can be synthesized by the asymmetric (11) Flamant-Robin, C.; Wang, Q.; Chiaroni, A.; Sasaki, N. A. Tetrahedron 2002, 58, 10475.
Org. Lett., Vol. 11, No. 18, 2009
and direct Michael reaction of nitroethanol and R,β-unsaturated aldehydes catalyzed by diphenylprolinol silyl ether as an organocatalyst, followed by isomerization. Good diastereoselectivity and excellent enantioselectivity have been obtained for a broad range of R,β-unsaturated aldehydes. We have also demonstrated that the products are useful synthetic intermediates with functional groups, which were successfully converted into chiral tetrahydropyran with a quaternary stereocenter, 3-substituted cis- and trans-prolines, and R-amino acid derivatives. Acknowledgment. This work was partially supported by a Grant-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science, and Technology (MEXT). Supporting Information Available: Detailed experimental procedures, full characterization, copies of 1H and 13C NMR and IR spectra of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. OL901483X
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